The Candidate has a long-term interest in the pathobiology of genetically modified mice. His training in human pathology and extensive experience in murine pathobiology permit for a comprehensive biomedical evaluation of novel mouse models, and constitute strong qualifications for the training of beginning mouse pathobiologists. The Award will free 50 percent of the Candidate's effort, thereby allowing him to: 1) increase his mentoring of beginning investigators; and 2) conduct ongoing research projects in the most effective manner. The immediate beneficiaries of this increase in the Candidate's mentoring are seven pathology residents at the department, as well as three postdoctoral fellows, one graduate, and five undergraduate students in the Candidate's laboratory. Additionally, the PI will extend his active training of beginning investigators to a number of collaborating laboratories. He will establish a training program in contemporary pathobiology of genetically modified mice at the College of Veterinary Medicine (CVM) at CU, and actively participate in national training forums. In his research, the Candidate will extend testing his earlier hypothesis that inactivation of the Rb results in preferential formation of neoplasms with neuroendocrine differentiation in mice. Towards this goal, the following Specific Aims are proposed: 1) to test the hypothesis that selective prevention of neoplasia in the pituitary and thyroid glands will result in preferential formation of other spontaneous tumors with neuroendocrine differentiation; 2) to test the hypothesis that targeted homozygous deletion of Rb in mouse tissues will preferentially result in neoplasia with neuroendocrine differentiation; and 3) to evaluate the hypothesis that Rb inactivation may have both synergistic and antagonistic effects on progression of neoplasia as a function of target cell type. These studies shall lead to our better understanding of mechanisms defining cell type-specific roles of Rb, lay a solid foundation for developing valid mouse models of neuroendocrine neoplasia associated with Rb deficiency, and provide numerous opportunities for training of beginning investigators. Taken together, freeing the Candidate's time from unrelated duties will greatly facilitate his efforts towards mentoring and productive research in the pathobiology of genetically modified mice.